The p63 protein, a member of the p53 family, is expressed in three major forms, p63a, p63b, and p63g. All three forms can be transcribed from a promoter located in intron 3, producing DNp63a, DNp63b, and DNp63g. p63 shares considerable sequence identity with p53, especially in the DNA binding, transactivation, and tetramerization domains. Like p53, p63 is a transcription factor capable of inducing cell cycle arrest, differentiation, and apoptosis. However, unlike p53 that plays an essential role in tumor suppression, p63 appears to be necessary for the maintenance and regeneration of epithelial stem cells. p63 deficiency in mice and heterozygous germline p63 mutations in humans lead to defects in limb, craniofacial, and epidermal morphogenesis. Recently, we showed that p63a and DNp63a differentially regulate p21, GADD45, and the p53 inducible gene 3 (PIG3). Furthermore, our preliminary data indicated that several genes, including plasminogen activator inhibitor 1 (PAl-l) and insulin-like growth Factor binding protein 3 (IGFBP3), are differentially regulated by various p63 isoforms. Since the transcriptional activity is necessary for p63 activity, we hypothesize that various p63 isoforms differentially regulate their target genes, which mediate the activity of p63 in inducing cell cycle arrest, differentiation, and apoptosis and are responsible for the distinct biological functions of p63. To further address these, we propose: (1) to identify and characterize novel target genes differentially regulated by various isoforms of p63; (2) to identify a p63-associated protein(s) that interacts with the sterile alpha motif (SAM) in p63 and is responsible for the differential gene regulation by the alpha and gamma variants of DNp63; and (3) to determine the mechanism by which some p63 isoforms differentially regulate the expression of p21, GADD45, IGFBP3, PIG3, and possibly, other novel p63 target genes.